Cycloalkenyl halogenated hydroxycinnamic acids



Patented Nov. 14, 1950 CYCLOALKENYL HALOGENATED HYDROXYCINNAMIC ACIDS Erwin Schwenk, Montclair, N. J., and Domenick Papa, Brooklyn, N. Y., assignors to Schering Corporation, Bloomfield, N. J a corporationof New Jersey No Drawing. Original application April 19, 1948, Serial No. 21,853. Divided and this application May 21, 1948, Serial No. 28,534

- 7 Claims. 1

The present invention relates to the manufacture of halogenated aryl alicyclic alkene and alkane carboxylic acids and their metal and amine salts.

It is a general object of the invention to produce halogenated compounds having useful chemotherapeutic properties. Other objects of the invention will appear as the more detailed description thereof appears.

We have found that in general the N-cycloalkene substituted acetic acid and the homologous acids and the corresponding isomeric cycloalkylidene carboxylic acids, having in the a-position to the carboxylic group either a methylene radical or the group :CH- (in the case of acetic acid), for example cyclohexenyl, cyclohexylidene, cyclopentenyl, cyclopentylidene, dihydronaphthyl and analogous acetic acids, and likewise the members of the acetic acid series substituted by terpene or terpene-like radicals having a double bond connected to the nuclear carbon linked to the acid group, can be condensed with a hydroxy aldehyde wherein the double bond of the aldehyde group forms part of a conjugated double bond system, the phenyl nucleus containing or being free from halogen atoms, to form dicylic alkene carboxylic acids which may be subsequently saturated in the alkene chain and in the cycloalkene ring; and these products are treated with halogenating agents if none of the starting compounds contained halogen. Among the starting aldehydes may be mentioned hydroxy-benzaldehydes, hydroXy-iodo-benzaldehydes, hydroxy-bromo-benzaldehydes, hydroxy-chloro-benzaldehydes, and the corresponding cinnamaldehydes.

As just indicated, the compounds of the present invention may be produced either by the halogenation of the aryl alicyclic alkene and a1- kane carboxylic acids having a hydroxyl-substituted benzene radical, or by forming the dicyclic compounds from starting compounds which already contain halogen. In the first procedure, compounds which may be produced in accordance with the process described in our copending application entitled Aryl-Alicyclic Carboxylic Acids and Process for Their Manufacture, Serial No. 544,831, filed July 13, 1944, now abandoned, are subjected to a known halogenation treatment. In proceeding in accordance with the second mode of manufacture, halogenated aromatic aldehydes, for example 3,5-diiodo-4-hydroxy-benzaldehyde, or the corresponding cinnamaldehyde, may be condensed with cycloalkene carboxylic acids or the corresponding cycloalkylidene carboxylic acids (in the form of their alkali metal salts).

Thus in making the compounds of the invention by the first-mentioned procedure, p-hydroxybenzaldehyde may, for example, be condensed by the Perkin reaction, or by modifica- 5 tions of the Perkin reaction, with a salt of cyclohexenyl acetic acid, such as the potassium or sodium salt, under anhydrous conditions in the presence of acetic anhydride, or in the form of the free acid and with the aid of a catalyst, for example, a tertiary amine like triethyl or tributyl amine, and the resulting a-(A -cyclohexenyl) -p-hydroxycinnamic acid may then be carefully hydrogenated, as by means of hydrogen and Raney nickel catalyst, and thereafter 10011-7 nated by known reagents to yield a-cyclohexyl- ,6 (3,5-diiodo-4-hydroxy-phenyl)propionic acid according to the following equation:

In the alternative procedure, by employing, for example, 3,5-diiodo-4-hydroxybenzaldehyde as one of the starting materials, the compound OOOH can be readily obtained. Cautious hydrogenation of this compound will yield the same product as mentioned above.

Analogous compounds are produced by employing other aldehydes such as 2,4,6-triiodo-5- hydroxybenzaldehyde, 3,5 dichloro-4-hydroxy benzaldehyde and the corresponding derivatives of cinnamaldehyde and higher aromatic aldehydes wherein the double bond of the aldehyde group is part of a conjugated double bond systerm.

The invention will be further described with the aid of the following examples which are presented only for purposes of illustration:

EXAMPLE I ad -cyclohezrenyu 3,5 -diiodo-4-hydro;ry-

cinnamic acid A mixture of 17.9 g. of anhydrous potassium cyclohexylidene acetate, 37.4 g. of 3,5-diiodo- 4-hydroxybenzaldehyde and 100 cc. of acetic anhydride is heated for 20-30 hours at 105-110 C. The condensation is run under anhydrous conditions. After the reaction mixture has cooled to about 60 C. The excess acetic anhydride is decomposed cautiously with water and the reaction mixture poured on ice. The semi-solid residue is extracted with ether and the acidic fraction isolated by means of sodium carbonate extraction. The sodium carbonate extracts are freed of ether, cooled and acidified to Congo red paper with I-ICl. The pale yellow precipitate is then recrystallized from a mixture of water and acetone and the substituted cinnamic acid is obtained in the form of a very pale yellow solid, melting at 212 C. with decomposition.

EXAMPLE II a.- (A -Cycloheccenyl) 3-z'odocz'nnamic acid 12 g. of 3-iodobenzaldehyde and 9 g. of anhydrous potassium cyclohexylideneacetate are condensed in acetic anhydride as described in Example I. After working up the reaction mixture, the iodinated acid is obtained from acetonewater mixture as a pale yellow solid melting at 169-1'70 C. This condensation can also be effected by using the isomeric potassium A -cyclohexenylacetate.

EXAMPLE III (3,5 -Diiodo-4-hydroxyphenyl) a-cycloheccylpropionic acid This acid is prepared by first condensing p-hydroxybenzaldehyde and anhydrous potassium cyclohexylideneacetate in acetic anhydride. The resulting a(A -cyclohexenyl) 4 hydroxycinnamic acid is reduced by any of the standard methods, and the hydrogenated compound iodinated as follows: To 0.1 m. (24 g.) of this hydrogenated acid dissolved in 800 cc. of

sodium hydroxide there is added a solution of 50.8 g. of iodine and 50.8 g. of KI dissolved in 250 cc. of water. The iodination reaction mixture is allowed to stand for one-half hour and then treated with sodium bisulfite solution. On acidification with concentrated HCl, the 3(35- diiodo 4 hydroxyphenyl) a-cyclohexylpropionic acid is obtained in a yield of 50 g., melting at 145-146" C. Recrystallization from acetone and water gives a product melting at 155-156 C.

EXAMPLE IV 13- (3,5-Dii0do-4-hydroxyphenyl) -a-cyclopentylpropionic acid 23.4 g. (0.1 m.) of a-(cyclopentyl)-B-(p-hydroxyphenyDpropionic acid is iodinated as described in Example III. The p-(3,5-diiodo-4- hydroxyphenyl)-a-cyclopentylpropionic acid is obtained in the form of a white crystalline powder which on recrystallization from acetone-water mixture melts at 131-132 C.

EXAMPLE V In similar fashion, a-(3,4-dihydro-6-methoxy- (cc) -naphthyl) 3,5-diiodo-4-hydroxycinnamic acid is obtained by reacting the potassium salt of 3,4-dihydro-6-methoxy- (a) -naphthy1acetic acid with 3,5-diiodo-4-hydroxybenzaldehyde in the presence of acetic anhydride. The product is isolated as described in Example I and after recrystallization from chloroform-petroleum ether melts at 112-114 C. with decomposition.

EXAMPLE VI The syntheses as outlined in Examples I to V can be modified to avoid the use of the anhydrous alkali salts. This modification uses the free acid, cyclohexenyl, cyclopentenyl, and other alicyclic acetic acids with the appropriate aromatic aldehyde together with suitable catalysts, i. e., triethyl amine, anhydrous sodium or potassium acetate, anhydrous potassium carbonate, etc.

28 g. (0.2 m.) of cyclohexenylacetic acid, 24.4 g. (0.2 m.) of p-hydroxybenzaldehyde, 20.2 g. (0.2 m.) of triethylamine and 61.2 g. (0.6 m.) of acetic anhydride are heated for 10-12 hours at MiG- C. The reaction mixture is worked up as described above, yielding u-(n -cyclohexenyl) 4-hydroxycinnamic acid which is then iodinated to the 3,5-diiodo-4-hydroxy compound.

The corresponding aliphatically compound of the formula saturated a-((i-methoxy-(a)-telralyl)-/3-(3, 5-diiodo-i-hydroxyplienyl)- propionic acid can be prepared by first reacting anhydrous potassium 3,4 dihydro 6 methoxy a-naphthyl acetate with 4-hydroxybenzaldehyde, followed by hydrogenation of the alicyclic ring and of the aliphatic chain, after which the intermediate is subjected to iodination.

In similar fashion, by the following series of reactions u-(3-isopropyl-6-methyl-A -cyclohexenyl)-3,5-diiodo-4hydroxycinnamic acid (I) and a (3-isopropyl-6-methylcyclohexyl) 43- (3,5- diiodo-4-hydroxyphenyl)propionic acid (II) can be prepared from the corresponding terpene compounds and diiodo-hydroxyand hydroxybenzaldehyde respectively:

CH3 on I CHzCOOH r I l H t V l /C& CH0 CH3 CH3 COOH OH I CH2C O OH H2 and r I CHO JH Cs OHs CHCH2OH 30011 1 Cg CHa EXAMPLE VII oc-CZ/ClOhGIl/l-,8- 3,5 -dibromo-4-hydroccyphenyl) propionic acid EXAMPLE VIII 'l y l (3,5 dichZoro-4-hydrowyphenyhpropz'omc acid This compound is prepared in accordance with the instructions of Example VII, except that 7.1 g. of chlorine dissolved in 100 cc. of acetic acid is substituted for the bromine solution. The dichloro acid after recrystallization from aqueous ethanol melts at 173.5-1'74.5 C.

EXAMPLE IX a (A -Cyclohexenyl) 3,5 dichloro-4-hydroxycinnamz'c acid A mixture of 0.1 m. of cyclohexanol-l-acetic acid, 0.1 m. of 3,5-dichloro-4-hydroxybenzaldehyde, 0.3 m. of anhydrous triethylamine and 150 cc. of acetic anhydride is heated for 72 hours at 105-1 C. The reaction mixture is then Worked up as described with the corresponding diiodo compound and purified by recrystallization from benzene-petroleum ether, melting point 194- 195 C.

EXAMPLE X a-(A -cyclohezcenyl) 3 chloro 4 hydroxycz'nnamz'c acid By substituting 3chloro 4 hydroxybenzaldehyde for the dichloro-aldehyde of the previous example, there may be obtained the monochloro derivative which is purified by recrystallization from aqueous ethanol.

EXAMPLE XI a-CycZopentyl-fi-(3,5-dibromo 4 hydroccyphenyDpropz'onic acid a-Cyclopentyl 5 (p-hydroxyphenyl) propionic acid is brominated exactly as described for the homologous cyclohexyl compound. It may be recrystallized from aqueous alcohol or a mixture of chloroform and petroleum ether.

The condensation products above described methods of neutralization or double decomposi-' tion. The amine salts, such as the diethyl amino ethanol salt, the mono-, di-, and triethanol amine salts and likewise the salts of other non-toxic amines can be prepared by combining equimolecular proportions of the substances in suitable solution followed by precipitation or crystallization.

The compounds of the invention possess bactericidal and amebicidal properties and are particularly useful in the treatment of amebic infections of the alimentary tract as their bactericidal properties aid in alleviating the secondary bacterial infections which are a common concomitant of amebiasis. pounds of the invention are also useful as X-ray contrast agents, and they are particularly valuable for oral administration for cholecystographic examination. They are substantially less toxic than the contrast agents heretofore available for X-ray examination of the gall bladder and they have the additional advantage that their bactericidal activity is useful in combating infections of the gall bladder so that they possess a double utility when employed as contrast agents.

This application is a continuation-in-part of our application Serial No. 544,832, filed July 13, 1944, now abandoned, and a division of our application Serial No. 21,853 filed April 19, 1948, and contains subject matter in common with our applications Serial No. 629,916, filed November 20, 1945, now Patent No. 2,516,153, Serial No. 722,084, filed January 14, 1947, now abandoned, and Serial No. 784,310, filed November 5, 1947, now abandoned.

We claim:

1. a-Cycloalkenyl-p-hydroxycinnamic acid substituted in at least one of the position ortho to the hydroxyl by a halogen having an atomic number not less than 17 and not more than 53.

2. a-Cycloalkenyl-p-hydroxycinnamic acid substituted in at least one of the positions ortho to the hydroxyl by iodine.

3. a-(A -Cyclohexenyl) 3,5-diiodo 4 hydroxycinnamic acid.

4. a (A Cyclohexenyl) 3,5 dichloro 4 hydroxycinnamic acid.

5. Process for the manufacture of dicyclically substituted aliphatic acids, which comprises heating and condensing a member of the group consisting of alicyclically substituted acetic acids and their salts, wherein the l-carbon of the alicyclic ring has a double bond connected thereto and wherein the alicyclic ring has from 5 to 6 carbon atoms, with p-hydroxybenzaldehyde substituted in at least one of the positions ortho to the hydroxyl by a halogen having an atomic number not less than 17 and not more than 53 under substantially anhydrous conditions and in the presence of the anhydride of a lower fatty acid to produce an alicyclically and aromatically substituted alkene carboxylic acid.

6. Process for the manufacture of dicyclically substituted aliphatic acids, which comprises heating and condensing a member of the group consisting of alicyclically substituted acetic acids and their salts, wherein the l-carbon of the alicyclic ring has a double bond connected thereto and wherein the alicyclic ring has from 5 to 6 carbon atoms, with a 3,5-diiodol-hydroxybenzaldehyde under substantially anhydrous conditions and in the presence of the anhydride of a lower The iodine-containing com- 1 2,529,518 7 8 fatty acid to produce an alicyclically and aro- UNITED STATES PATENTS matically substituted alkene carboxylic acid. Number Name Date 7. a-(A -cyclohexenyl) -3-ch1or0 4 hydroxy- 2 400 433 Natelson et a1 May 14 1946 cinnamic acid.

OTHER REFERENCES Faltis et a1.; Liebigs Annalen, vol. 497, pp. 70- 88 (1932) ERWIN SCHWENK. 5 DOIVLENICK PAPA.

REFERENCES CITED The following references are of record in the file of this patent: 

1. A-CYCLOALKENYL-P-HYDROXYCINNAMIC ACID SUBSTITUTED IN AT LEAST ONE OF THE POSITIONS ORTHO TO THE HYDROXYL BY A HALOGEN HAVING AN ATOMIC NUMBER NOT LESS THAN 17 AND NOT MORE THAN
 53. 